It is known that enkephalin or endorphine as the analgesic peptide exists in the brain of mammalian animals and particularly enkephalin is existing at a high level in the vesicles of the nervous cells at the nerve ending of the nerve fibre in the brain, and also that enkephalinase is co-existing in the same areas as those where the enkephalin is found. Besides, the possibility that enkephalin functions as neurotransmitters in the central nervous system of mammalian animals is suggested in the "Nature" Vol. 276, pages 523 to 526 (1980).
Furthermore, it has been revealed that acupuncture analgesia is mediated through release of the analgesic peptides such as enkephalin in the brain when the effectiveness of acupuncture analgesia was examined by measuring tail-flick latency of rats while the contents of the analgesic peptides in the brain were determined (see the Japanese medicinal journal "Showa Igakukai Zasshi" Vol. 39, No. 5, pages 537 to 542 (1979). It is also reported that the analgesic activity of morphine is relying on that morphine plays a role to cause enkephalin to be released in the nervous system (see the "Life Science" No. 25, pages 53 to 60 (1979)).
We have taken the above facts into consideration and we take it that generally, an inhibitor against enkephalinase will show an analgesic activity when it is used alone and it is expected that the inhibitor against enkephalinase will be highly effective for eliminating or minimizing the pain of such patients who feel chronic pain owing to a low level of enkephaline in the brain. In view of the disclosure in the "Showa Igakukai Zasshi" Vol. 39, No. 5, pages 543 to 550 (1979), it is also expected that an enkephalinase-inhibitor will be useful as an aid for enhancing the acupuncture analgesia and morphine analgesia, and that such enkephalinase-inhibitor, even alone, will be effective to change the acupuncture-ineffective patients into the acupuncture-effective patients.
In an attempt to provide a new analgesic agent, therefore, we extensively researched on the inhibitory activity of many known compounds against enkephalinase, the enzyme of degrading enkephalin. As a result, we previously found that 3-amino-2-hydroxy-4-phenylbutanoic acid and some related compounds thereof have the enkephalinase-inhibiting activity in vitro and, when tested in animals, exhibit the analgesic activity in vivo. Based on these previous findings, we devised an invention which relates to an analgesic agent comprising as the active ingredient (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid (abbreviated as AHPA), its amide, its methyl ester, (2R,3R)-3-amino-2-hydroxy-4-phenyl-1-butanol or a dipeptide compound represented either by a formula ##STR1## wherein R' is selected from D-leucine residue, D-glutamic acid residue, D-alanine residue, D-arginine residue, D-methionine residue, L-methionine residue, .beta.-alanine residue, D-asparatic acid residue and glycine residue, or by a formula ##STR2## wherein R" is selected from D-leucine residue, L-leucine residue and D-phenylalanine residue (see Japanese patent application No. 131583/1980; U.S. patent application Ser. No. 303,938; U.K. patent application No. 8128604).
The compounds as mentioned above have such a moiety in their chemical structure which is common to that of bestatin, namely (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl-(S)-leucine (see U.S. Pat. Nos. 4,029,547 and 4,189,604), and hence they may be said to be bestatin-related compounds in brief.
In a further development of our study, we have now succeeded to synthetize a number of new 3-amino-2-hydroxy-4-phenylbutanoic acid derivatives of a kind different from the above-mentioned known bestatin-related compounds. For the screening purpose, we have tested these new derivative compounds for their activity inhibitory to enkephalinase, the enzyme of degrading the enkephalin. As a result of our screening test, we have now found that amongst the new compounds now synthetized by us which are active as the inhibitor of enkephalinase, the new compounds of the general formula (1) shown below exhibit a significant analgesic activity in animal tests. Thus, we have reached this invention.